The invention relates to antigenic constructs resulting from the linkage of major histocompatibility complex (MHC) class I antigens with specific carrier molecules.
Tissue-rejection reactions are the strongest-known immune responses mediated by T cells. In individuals of the same species they are caused by allogenic differences in class I and class II MHC antigens. In organ transplants, for example, any allogenic determinants of the MHC antigens present in the donor tissue are recognized as foreign by allospecific T cells of the recipient, a T cell immune response is induced, and the rejection reaction takes place unless an immunosuppressive therapy has been initiated or such a therapy proves insufficient.
It is furthermore known that MHC class I antigens are glycoproteins which are expressed on the surface of all nucleated cells. They are composed of a heavy chain, which is encoded by MHC class I genes, and of a light chain, the xcex22-microglobulin which is non-covalently associated with the heavy chain. The extracellular part of the heavy chain is folded in three domains, the first two of these domains (alpha1 and alpha2) exhibiting a pronounced polymorphism when the amino acid sequences of hitherto known class I MHC antigens from various individuals are compared. They assist with antigen presentation and carry the allogenic determinants. The third extracellular domain has a more conserved sequence. The association with xcex22-microglobulin is essential for correct folding of the heavy chain and for the transport of the molecule to the cell surface.
Isolation and characterization of mutated MHC class I antigens in mice showed that merely a few differences in amino acids on the alpha1 and alpha2 domains between donor and recipient suffice to induce a rejection reaction (Nathenson et al., Ann. Rev. Immunol., 1986, 4, 471-502). It has also been shown in humans that slight differences between donor and recipient lead to rejection of a transplant (Dausset, J., Rapaport, F. T., Legrand, L., Colombani, J., Marcelli-Barge, A.: Skin allograft survival in 238 human subjects: Role of specific relationships at the four gene sites of the first and the second HL-A loci., Histocompatibility Testing (1970) pages 381-397, Terasaki P. I. (Ed.)). The task which presented itself from that said above was to utilize the specific inducibility and strength of the cellular immune response in the tissue-rejection reaction to damage or destroy selected target cells.